Download Q&A: Evolutionary capacitance Open Access Joanna Masel

Masel BMC Biology 2013, 11:103
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QUESTION AND ANSWER
Open Access
Q&A: Evolutionary capacitance
Joanna Masel
What is an evolutionary capacitor?
Many mutations are conditionally neutral: important
under some conditions, invisible at other times. Capacitors
are on/off switches affecting the visibility of a particular
set of conditionally neutral variants. While in the neutral
state, ‘cryptic’ genetic variants can drift to high frequency;
extending the electrical analogy, accumulated cryptic
variants can be seen as a kind of genetic ‘charge’ [1].
Can you give an example of what cryptic variants
are and what turns their phenotypic effects on?
Yes. When yeast ribosomes reach a stop codon, the protein Sup35 helps terminate translation. The Sup35 protein can switch between two conformations, which share
an identical amino acid sequence. The normal form is
soluble, while the [PSI+] prion form sucks Sup35 up into
aggregates. With less soluble Sup35 available, translation
can occasionally continue beyond the stop codon, so
that extra amino acids are added onto the growing protein’s carboxyl terminus. The nucleotides beyond the
stop codon are ‘cryptic’ because they were there all
along, but normally their precise identity doesn’t matter.
They are only translated into amino acids when the capacitor [PSI+] is present. Capacitance, in this case, is the
consequence of a yeast lineage being able to switch between [PSI+] and [psi-].
Isn’t it really bad for the yeast to read through
stop codons?
Yeast tolerate [PSI+] remarkably well, and not just under
lab conditions: the prion is seen in the wild, too [2].
Even when [PSI+] is present, most proteins still terminate normally. But [PSI+] does make a big difference to
the phenotype, depending on exactly which cryptic variants are present in a given strain [2,3]. [PSI+] is relatively rare in wild yeast strains, so most of the time it is
probably bad for yeast [4]. But [PSI+] increases variation,
so it might have a positive effect some of the time. On
Correspondence: [email protected]
Ecology and Evolutionary Biology, University of Arizona, 1041 E. Lowell St,
Tucson, AZ 84721, USA
those occasions, [PSI+] can smooth the path to adaptation. By providing this smoothing, evolutionary capacitors act as adaptive devices or ‘widgets’ [5] that increase
evolvability, defined as the rate of appearance of heritable and potentially adaptive phenotypic variants [6].
Isn’t that a pretty extraordinary claim in
evolutionary biology?
Actually, the logic and math of the evolution of a capacitance switch is identical to that of the well-accepted case
of bet-hedging [7]. The seeds of annual plants don’t all
germinate straight away. If they did, and it was a bad
year, the plant lineage would get wiped out. It’s better
for a plant to pay a cost to hedge its bets, and have some
seeds germinate while others lie dormant. Dormancy is a
bet on a bad season; evolutionary capacitor switching is
a bet on finding adaptive cryptic variants in a new
environment.
So the switching is completely random?
We don’t understand exactly how switching happens,
but we do know that the probability of switching goes
up when the yeast is under stress [8]. When everything
is going well, increasing variation will be bad both for
the average yeast cell, and for the population as a whole.
But in a new and stressful environment, there’s a better
chance that change introduces an adaptation into the
population.
How is the new phenotype inherited?
At first, the new phenotype is only present when [PSI+]
is present. Prions like [PSI+] are inherited epigenetically,
via the cytoplasm [9]. In a phenomenon known as ‘genetic assimilation’, a trait that was originally non-genetic
can become genetic after some generations of selection
[10]. As explained earlier, even in the presence of [PSI+],
any given stop codon is not always read through to express the cryptic variant; this partial nature of the
readthrough presumably weakens the variant’s phenotypic effects. Selection can favor changes, such as mutations in stop codons [11], that both increase the
expression level of the adaptive variant, and cause it to
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Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
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Masel BMC Biology 2013, 11:103
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lose its initial dependency on the presence of [PSI+]
[12]. Then the prion can disappear again. The [PSI+]
prion can help the yeast lineage survive long enough to
find these genetic assimilation mutations [6], or it can
simply help the lineage get to the final [psi-] adaptation
faster through a more efficient adaptive path [12]. Unlike
the case of mutator alleles, or a mutation partially
knocking out Sup35 function, there is no long-term cost
involved when capacitance increases the rate of adaptation [13]. The prion acts as a stopgap, finding an adaptive variant quickly, allowing its short-term inheritance,
and disappearing again once the phenotype is more stably assimilated into the DNA. Lineages that are able to
switch in and out of the [PSI+] state have an advantage
over those that can’t, even if the [PSI+] state itself carries
a cost [4].
The [PSI+] prion is pretty weird and obscure. Can
you give a more general example?
The most famous example is loss of function of the
chaperone Hsp90 [14,15]. Hsp90 stabilizes many metastable signal transducers. When an organism is in trouble,
Hsp90 may have too much work to do, mimicking a partial deletion. This has unpredictable consequences, depending on which cryptic variants are present in that
individual’s genetic background, both in direct Hsp90 client proteins that may destabilize in the absence of Hsp90,
and in genes downstream of the clients in signal transduction pathways.
For how many generations does Hsp90 stay
impaired?
That’s a good question. For Hsp90 or other evolutionary
capacitors to have a significant impact on evolvability,
cryptic variants need to stay switched on long enough
for genetic assimilation to take place [12,16]. We don’t
know if this is the case for Hsp90-mediated variation.
Are most capacitors chaperones?
Probably not. Models of gene regulatory networks suggest that any reversible knockout - for example, as may
be the result of the protein forming a prion - can act as
an evolutionary capacitor [17]. Even irreversible knockouts, such as gene deletions, can facilitate adaptation
[17]. Mutations to chromatin regulators [18] and other
regulatory genes [19-21] reveal substantial cryptic variation. Yeast knockouts were screened for genes that provide robustness to normal developmental perturbations
[22]; these genes (sometimes known as ‘phenotypic stabilizers’ rather than capacitors because they have not yet
been shown to provide robustness to mutations [23]) are
enriched for a number of gene types, but not chaperones. An unbiased screen of genomic regional deletions
in Drosophila found many new sites whose deletion
Page 2 of 4
reveals cryptic genetic variation, but Hsp90 was not
among them [24]. There may be so many potential capacitors out there that rather than capacitance being a
‘special’ mechanism, cryptic standing (or ‘crouching’)
genetic variation may make routine contributions to
adaptation [25].
So capacitor genes provide mutational
robustness, which is lost in the knockout?
The phenotypes of mutants such as gene knockouts are
more variable than the phenotypes of the wild type [26],
but this does not necessarily reflect mutational robustness. It does demonstrate the high robustness provided
by the gene to the microenvironmental perturbations
inherent in normal developmental processes. Robustness to mutations is more complicated, as shown in
Figure 1. In the capacitance story, a knockout reveals
genetic variants, showing that the intact gene provided
robustness to those variants. But the knockout can also
hide variants that would otherwise matter, in which case
the gene is called a potentiator rather than a capacitor
[27,28]. Considering both effects together, knockouts
may be no less robust to mutations than wild types are
[21]. But even when a gene does not increase robustness
to mutations overall, it will still make some specific
mutations cryptic, allowing them to accumulate until
the capacitor discharges [29]. In other words, capacitors
are best defined as genes with many epistatic interactions (in the classical genetic sense in which an allele at
one locus masks the effect of a polymorphism at
another), rather than as genes that increase mutational
robustness.
What’s so good about cryptic variation?
The distribution of fitness effects of new mutations is bimodal (Figure 2); most mutations either destroy something, or they tinker with it (in other words, have only
small fitness effects), but their effects are rarely inbetween [30]. Adaptation comes entirely from the tinkering mutations. Cryptic variants are special because
they have a higher proportion of tinkering variants and
fewer lethal ones. This is because there is a sharp threshold for the effectiveness of selection s that depends on
the effective population size Ne; when this threshold is
exceeded (which is when s > 1/Ne), selection works
great, otherwise evolution is neutral. When genetic variants spend time in a cryptic state, they are usually
expressed just a tiny bit. In other words, conditional
neutrality in practice usually means conditional nearneutrality. This slight deviation from strict neutrality is
enough to purge the destructive variants but retain the
tinkering ones, which accumulate until the capacitor
comes along to release them [31,32].
Masel BMC Biology 2013, 11:103
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Page 3 of 4
Figure 1. In the red section of the genome (left), the gene acts as a capacitor, allowing cryptic genetic variation to accumulate. In the
black section of the genome, variation is fully expressed, and most is purged. When the gene is knocked out, abundant cryptic genetic variation
is revealed, and a smaller amount of previously expressed variation is made cryptic. The red and black sections are shown as equally large,
indicating that the wild type is not necessarily more robust to new mutations, on average, than the knockout [21].
frequency
frequency
new mutations
formerly cryptic
mutations
fitness
Figure 2. The distribution of fitness effects of new mutations is
bimodal (top). While in a partially cryptic state, selection is strong
enough to purge the left mode, while having little effect on the
right mode, generating a set of cryptic variants of greatly enriched
quality (bottom).
So the advantage of cryptic genetic variation is
the quality, not the quantity?
Cryptic genetic variation has both quality and quantity advantages [33]. As for quantity, capacitance helps time the
release of genetic variants to coincide with episodes of
stress. Because lots of variants lose their crypticity at the
same time, evolution can also explore more combinations
and so cross more valleys in adaptive landscapes [16,31].
Do recessive alleles count as cryptic variants?
Sure, when an allele usually finds itself in a heterozygote,
its recessive effects are cryptic to selection. In mostly asexual populations, excess heterozygosity can build up during
an asexual phase, and rare episodes of sex will then act as
a capacitor: outcrossing explores new allele combinations
[34], while inbreeding increases phenotypic variation by
converting heterozygotes to homozygotes [35]. In obligate
sexuals, hybridization can have similar effects [36]. But
unlike the changes brought about by a prion switch or a
temporary gene downregulation, the changes brought
about by sex are not so easily reversible. Sex releases cryptic variation in a single generation, but making it cryptic
again is slower and more difficult. Unlike [PSI+], the capacitance switch only goes one way.
Acknowledgements
I thank Jay McEntee, Mark Siegal, and Liang Wu for helpful comments on the
manuscript. JM is supported by NIH R01GM104040 and by the John
Templeton Foundation.
Published: 30 September 2013
Masel BMC Biology 2013, 11:103
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doi:10.1186/1741-7007-11-103
Cite this article as: Masel J: Q&A: Evolutionary capacitance. BMC Biology
2013 11:103.